1. Field of the Invention
The invention relates to a process for preparing enantiomerically enriched aryl-amino-propanols and to their use and also to intermediates.
2. Description of Related Art
1-Aryl-3-aminopropan-1-ols have gained industrial significance in particular as intermediates for the preparation of pharmaceuticals. For example, some 1-aryl-3-aminopropan-1-ols serve as precursor substances for the preparation of seratonin or noradrenalin takeup inhibitors. In the case of some of these inhibitors, it could be proven that certain enantiomers are not only inactive or less active, but may also even exhibit undesired side effects (U.S. Pat. No. 5,104,899).
Corey and Reichard (Tetrahedron Letters, 39, 5207, 1989) describe a process for preparing S-fluoxetine in which, in an important step, 3-chloropropiophenone is asymmetrically reduced using a chiral borane to give S-3-chloro-1-phenyl-1-propanol.
After reaction with sodium iodide and methylamine, (S)-3-(methylamino)-1-phenylpropan-1-ol is then obtained which may then be reacted further to the end product. Disadvantages of this process are that expensive reagents have to be used, and that the overall yield is only 77 to 82%.
A process for preparing enantiomerically enriched (1S)-3-(methylamino)-1-(2-thiophen-yl)-1-propanol starting from 1-(2-thiophen-yl)-3-chloropropan-1-one is described in Chirality 2000, 12, 26-29. After the reduction to racemic 3-chloro-1-(2-thienyl)-1-propanol, the racemate is enzymatically separated and the (S)-enantiomer is further reacted with NaI and methylamine to give (S)-3-(methylamino)-1-(2-thiophen-yl)-propan-1-ol. This method has the disadvantage that enzymatic racemate separations can in principle only provide 50% of the desired enantiomer and the overall yield is therefore economically unacceptable.
A similar synthetic route is described in J. Lab. Comp. Radiopharm. 1995, 36, 213-223, in which 1-(2-thiophen-yl)-3-chloropropan-1-one is asymmetrically reduced with borane and an oxazaborolidine. The yield in this step is only 61%, which makes the overall process uneconomic.
There was therefore a need for an efficient and widely applicable process for preparing enantiomerically enriched arylaminopropanols which starts from reactants obtainable in a simple manner.